Elevated intracranial pressure causes optic nerve and retinal ganglion cell degeneration in mice.

The purpose of this study was to develop a novel experimental system for the modulation and measurement of intracranial pressure (ICP), and to use this system to assess the impact of elevated ICP on the optic nerve and retinal ganglion cells (RGCs) in CD1 mice. This system involved surgical implantation of an infusion cannula and a radiowave based pressure monitoring probe through the skull and into the subarachnoid space. The infusion cannula was used to increase ICP, which was measured by the probe and transmitted to a nearby receiver. The system provided robust and consistent ICP waveforms, was well tolerated, and was stable over time. ICP was elevated to approximately 30 mmHg for one week, after which we assessed changes in optic nerve structure with transmission electron microscopy in cross section and RGC numbers with antibody staining in retinal flat mounts. ICP elevation resulted in optic nerve axonal loss and disorganization, as well as RGC soma loss. We conclude that the controlled manipulation of ICP in active, awake mice is possible, despite their small size. Furthermore, ICP elevation results in visual system phenotypes of optic nerve and RGC degeneration, suggesting that this model can be used to study the impact of ICP on the visual system. Potentially, this model can also be used to study the relationship between ICP and IOP, as well diseases impacted by ICP variation such as glaucoma, idiopathic intracranial hypertension, and the spaceflight-related visual impairment intracranial pressure syndrome.

[1]  D. Sretavan,et al.  Laser-induced ocular hypertension in albino CD-1 mice. , 2010, Investigative ophthalmology & visual science.

[2]  A. Verkman,et al.  Mouse model of sustained elevation in intraocular pressure produced by episcleral vein occlusion. , 2006, Experimental eye research.

[3]  H. Quigley,et al.  The effects of anesthesia, mouse strain and age on intraocular pressure and an improved murine model of experimental glaucoma. , 2012, Experimental eye research.

[4]  J. Erichsen,et al.  A novel method for the induction of experimental glaucoma using magnetic microspheres. , 2011, Investigative ophthalmology & visual science.

[5]  H. Quigley,et al.  Calibration of the TonoLab tonometer in mice with spontaneous or experimental glaucoma. , 2011, Investigative ophthalmology & visual science.

[6]  John H. Zhang,et al.  New lumbar method for monitoring cerebrospinal fluid pressure in rats , 2004, Journal of Neuroscience Methods.

[7]  H. Quigley,et al.  The number of people with glaucoma worldwide in 2010 and 2020 , 2006, British Journal of Ophthalmology.

[8]  M. Fautsch,et al.  A Novel Rat Model to Study the Role of Intracranial Pressure Modulation on Optic Neuropathies , 2013, PloS one.

[9]  M. Nedergaard,et al.  ‘Hit & Run’ Model of Closed-Skull Traumatic Brain Injury (TBI) Reveals Complex Patterns of Post-Traumatic AQP4 Dysregulation , 2013, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  E. Nemoto,et al.  Effect of Cerebral Perfusion Pressure on Cerebral Cortical Microvascular Shunting at High Intracranial Pressure in Rats , 2013, Stroke.

[11]  H. Quigley,et al.  Differential susceptibility to experimental glaucoma among 3 mouse strains using bead and viscoelastic injection. , 2010, Experimental eye research.

[12]  M. Harirchian,et al.  The relation between intracranial and intraocular pressures: Study of 50 patients , 2006, Annals of neurology.

[13]  M. Monteiro,et al.  Macular thickness measurements with frequency domain-OCT for quantification of axonal loss in chronic papilledema from pseudotumor cerebri syndrome , 2014, Eye.

[14]  A. Harvey,et al.  Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons , 2003, Molecular and Cellular Neuroscience.

[15]  J. Jonas,et al.  Trans-lamina cribrosa pressure difference correlated with neuroretinal rim area in glaucoma , 2011, Graefe's Archive for Clinical and Experimental Ophthalmology.

[16]  Ronald L Gross,et al.  A mouse model of elevated intraocular pressure: retina and optic nerve findings. , 2003, Transactions of the American Ophthalmological Society.

[17]  John H. K. Liu,et al.  Circadian variations in intracranial pressure and translaminar pressure difference in Sprague-Dawley rats. , 2010, Investigative ophthalmology & visual science.

[18]  S. Stinnett,et al.  Cerebrospinal Fluid Pressure Decreases with Older Age , 2012, PloS one.

[19]  H. Quigley,et al.  Translimbal laser photocoagulation to the trabecular meshwork as a model of glaucoma in rats. , 2002, Investigative ophthalmology & visual science.

[20]  A. Criscuoli,et al.  Quantitative analysis of optic nerve damage in idiopathic intracranial hypertension (IIH) at diagnosis , 2013, Neurological Sciences.

[21]  Larry A Kramer,et al.  Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight. , 2011, Ophthalmology.

[22]  G. Silasi,et al.  Use of telemetry blood pressure transmitters to measure intracranial pressure (ICP) in freely moving rats. , 2009, Current neurovascular research.

[23]  Chris A. Johnson,et al.  The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. , 2002 .

[24]  Alan R Hargens,et al.  Intraocular/Intracranial pressure mismatch hypothesis for visual impairment syndrome in space. , 2014, Aviation, space, and environmental medicine.

[25]  John P Berdahl,et al.  Posterior Scleral Biomechanics and the Translaminar Pressure Difference , 2014, International ophthalmology clinics.

[26]  David J. Calkins,et al.  Distal axonopathy with structural persistence in glaucomatous neurodegeneration , 2010, Proceedings of the National Academy of Sciences.

[27]  S. Feldon,et al.  The idiopathic intracranial hypertension treatment trial: clinical profile at baseline. , 2014, JAMA neurology.

[28]  Xu Meng,et al.  Telemetric Intracranial Pressure Monitoring in Blast-Induced Traumatic Brain Injury , 2014, IEEE Transactions on Biomedical Engineering.

[29]  J. Horton,et al.  No correlation between intraocular pressure and intracranial pressure , 2008, Annals of neurology.

[30]  Richard M. McCarron,et al.  Measurement of blast wave by a miniature fiber optic pressure transducer in the rat brain , 2007, Journal of Neuroscience Methods.

[31]  L. Keil,et al.  Intracranial hypertension after cerebroventricular infusions in conscious rats. , 1990, The American journal of physiology.

[32]  A. Shekhar,et al.  Dorsomedial/Perifornical hypothalamic stimulation increases intraocular pressure, intracranial pressure, and the translaminar pressure gradient. , 2012, Investigative ophthalmology & visual science.

[33]  C. L. Schlamp,et al.  Mouse models of retinal ganglion cell death and glaucoma. , 2009, Experimental eye research.

[34]  Robert N Weinreb,et al.  Optic nerve damage in experimental mouse ocular hypertension. , 2003, Investigative ophthalmology & visual science.

[35]  Ji-Jie Pang,et al.  Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice , 2015, Proceedings of the National Academy of Sciences.

[36]  Ji-Jie Pang,et al.  Elevated intraocular pressure causes inner retinal dysfunction before cell loss in a mouse model of experimental glaucoma. , 2013, Investigative ophthalmology & visual science.

[37]  R. Allingham,et al.  Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma. , 2008, Ophthalmology.

[38]  Ji-Jie Pang,et al.  Morphology and immunoreactivity of retrogradely double-labeled ganglion cells in the mouse retina. , 2011, Investigative ophthalmology & visual science.

[39]  R. A. Solomon,et al.  A simple and reliable technique to monitor intracranial pressure in the rat: technical note. , 1992, Neurosurgery.

[40]  N. Plesnila,et al.  Standardized induction of subarachnoid hemorrhage in mice by intracranial pressure monitoring , 2010, Journal of Neuroscience Methods.

[41]  Chris A. Johnson,et al.  Baseline visual field findings in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). , 2014, Investigative ophthalmology & visual science.

[42]  Derek M Nusbaum,et al.  Prolonged elevation of intraocular pressure results in retinal ganglion cell loss and abnormal retinal function in mice. , 2015, Experimental eye research.

[43]  David J. Calkins,et al.  The microbead occlusion model: a paradigm for induced ocular hypertension in rats and mice. , 2010, Investigative ophthalmology & visual science.

[44]  S. Wu,et al.  Effects of elevated intraocular pressure on mouse retinal ganglion cells , 2005, Vision Research.

[45]  Elisha D O Roberson,et al.  Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model , 2008, The Journal of Neuroscience.

[46]  Robert N Weinreb,et al.  Optic neuropathy induced by experimentally reduced cerebrospinal fluid pressure in monkeys. , 2014, Investigative ophthalmology & visual science.

[47]  J. Acheson.  Idiopathic intracranial hypertension and visual function. , 2006, British medical bulletin.

[48]  Guochun Chen,et al.  Optic neuropathy due to microbead-induced elevated intraocular pressure in the mouse. , 2011, Investigative ophthalmology & visual science.

[49]  Young H. Kwon,et al.  Laser-induced mouse model of chronic ocular hypertension. , 2003, Investigative ophthalmology & visual science.

[50]  David J. Calkins,et al.  Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma , 2008, The Journal of Neuroscience.

[51]  G. Gole,et al.  Selective inner retinal dysfunction precedes ganglion cell loss in a mouse glaucoma model , 2008, British Journal of Ophthalmology.

[52]  J. Jonas,et al.  Cerebrospinal fluid pressure in glaucoma: a prospective study. , 2010, Ophthalmology.

[53]  T. K. Nam,et al.  Development of an acute obstructive hydrocephalus model in rats using N-butyl cyanoacrylate , 2011, Child's Nervous System.

[54]  Minocycline reduces reactive gliosis in the rat model of hydrocephalus , 2012, BMC Neuroscience.

[55]  M. Gordon,et al.  Association between visual parameters and neuroimaging features of idiopathic intracranial hypertension , 2013, Journal of the Neurological Sciences.

[56]  Sandra S Stinnett,et al.  Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study. , 2008, Investigative ophthalmology & visual science.